The final progression-free survival (PFS) and overall survival (OS) data from the OVA-301 phase III trial were presented by Dr. Bradley Monk of the Creighton University School of Medicine in Phoenix, AZ at a symposium highlighting the use of trabectedin in ovarian cancer at the ESGO Meeting in Milan, Italy on September 11, 2011. The data were presented as a poster at ASCO in 2011, but the ESGO meeting was the first time the data were presented as a speaker presentation.

The OS benefit of the combination of T+PLD in the pivotal study for all patients was a median of 3.2 months (P = .0285). The largest benefit was seen in the partially platinum-sensitive (PPS) ovarian cancer patient subset, with a 35% risk reduction of death compared to PLD alone (P = .0056).

The OVA-301 Trial Design

The OVA-301 enrolled 672 relapsed ovarian cancer patients from 2005 to 2008, randomized to T+PLD or PLD every 3 weeks given by IV infusion. The patients were stratified by the length of their platinum-free interval (PFI). The primary endpoint of the trial was PFS, with OS as a secondary endpoint.

A platinum-based chemotherapy regimen is typically the first-line treatment of advanced ovarian cancer and further treatment depends on whether the ovarian cancer is platinum-sensitive or platinum resistant. Platinum-sensitive ovarian cancer is defined as a relapse that occurs 12 months or more following platinum treatment. A PPS cancer is one with a PFI of approximately between 6 and 12 months. Patients whose disease relapses 6 months or sooner after platinum treatment are said to have platinum-resistant (PR) disease.

OVA-301 Results

After the final OS analysis at the end of 2010, the median follow-up of patients was 47.4 months. The median OS was 22.4 and 18.9 months for the combination and PLD groups, respectively (P = .0835). Because there was an imbalance in the PFI between the two arms that was unintended (10.6 months compared to 13.3 months PFI in the T+PLD vs PLD arms), the authors performed a multivariate analysis that was adjusted by PFI as a prognostic factor. This analysis showed a significant improvement in OS in patients treated with the combination, with a difference in median survival of 3.2 months (18% risk reduction, P = .0285). Although there was a consistent improvement in OS across all PFI groups (PS, PPS, and PR), the most pronounced difference was seen in the PPS subgroup. The decrease in risk of death between the combination and PLD arms was 36% (P = .0027), 17%, and 6% for the PPS, PR, and PS subgroups, respectively.

Because the effectiveness of the combination treatment correlated with the PFI, the OS results were reanalyzed for the PS and PPS subsets of patients in this trial. OVA-301 included 216 PS and 214 PPS patients. OS was 22.4 compared to 16.4 months in the combination versus PLD alone groups in PPS patients. For PS patients, the OS was 27.0 months compared to 24.1 months. This is the longest overall survival data of any clinical trial in this patient population, taking 4 years to complete.

PPS patients in the study were followed for survival until their death and analyzed based on their subsequent therapies after the OVA-301 trial regimens. Among the 214 PPS patients, 94 received a platinum-containing regimen directly after OVA-301. A superior median OS was seen among the 94 patients who had received the T+PLD combination as compared to PLD alone. The median OS was 27.7 months, compared to 18.7 months for T+PLD and PLD patients, respectively. This is a 43% risk reduction (P = .0153) in favor of the combination treatment. The authors conclude that PFI is a key prognostic factor in ovarian cancer and that the T+PLD combination shows an enhanced benefit in the PPS population. The T+PLD combination followed by a platinum regimen appears to be particularly beneficial, with a 9-month difference in OS compared to PLD alone followed by platinum. This analysis suggests that the PPS subset of patients may strongly benefit in the use of T+PLD as a second-line treatment followed by a platinum regimen in the third line.

Although these latest data are the result of ad hoc analyses following completion of the trial, they have shown a substantial benefit in the PPS population. The results have warranted a subsequent trial to test the hypothesis that PPS patients respond well to the T+PLD combination in second line.

Dr. Bradley Monk explained that "the salient point is that when trabectedin is added to liposomal doxorubicin, there appears to be a treatment effect. The statistical significance of that treatment effect on overall survival depends on the analysis. The analysis written in the protocol does not qualify for statistical significance, but when one recognizes the imbalance in the important prognostic factor platinum-free interval, it favors the liposomal doxorubicin control arm. It becomes clear that it is at least clinically relevant. It may not be statistically appropriate but it’s clinically relevant, but I think it's important to ask yourself ‘Is there a treatment effect?' and there is, here."

New Trial in PPS Patient Population

“The overall survival data in the partially platinum patients support the INNOVATYON trial, which has overall survival as the primary endpoint” noted Dr. Monk, during the session.

The INNOVATYON trial is a phase III superiority trial that will test the hypothesis that the T+PLD regimen is superior for the PPS patient population. The trial will randomize 588 patients to either T+PLD or carboplatin+PLD who have been treated with a platinum-based regimen and had a subsequent relapse within 6 to 12 months. The trial will follow patients for approximately five years.

Trabectedin (Yondelis) is an infused chemotherapy drug that is naturally occurring in the marine organism Ecteinascidia turbinate, a type of sea squirt. Trabectedin binds to the minor groove of DNA, interfering with cellular division and DNA repair machinery and causing apoptosis. Trabectedin is approved in Russia, South Korea, and Europe for advanced soft tissue sarcoma after failure of first-line treatment or in patients that are unsuitable for the indicated first-line regimen. It was the first drug in over 30 years to reach the market for this disease. It is in phase II clinical trials for pancreatic, prostate, and breast cancers. The European Commission (EC) approved the trabectedin plus pegylated liposomal doxorubicin combination for relapsed platinum-sensitive ovarian cancer in the European Union at the end of 2009, and is now approved in 26 additional countries, including Canada and Israel.

Pegylated liposomal doxorubicin (Doxil in the United States and Caelyx in Europe and other countries) is a pegylated liposome-encapsulated form of doxorubicin. Doxorubicin is an anthracycline antibiotic, a type of chemotherapy, which is commonly used to treat hematological cancers, different types of carcinoma, and soft tissue sarcomas. The pegylated formulation was developed to prevent the accumulation of doxorubicin in the skin. The original formulation causes hand-foot syndrome (palmar plantar erythrodysesthesia), characterized by redness, tenderness, pain, and peeling of the skin. The condition is caused by the leaking of the drug from capillaries in the palms of the hands and the soles of the feet.

The Trabectedin+PLD Combination Is Not Approved in the United States

While the results of the OVA-301 data led to approval in the European Union, Canada, and other countries, the FDA rejected the drug in 2010. The cited reasons for rejection included a general lack in the demonstration of an OS benefit in the population as a whole. It should be noted that the rejection came before the maturation of the full OS data and before the analysis of the PFI subpopulations.

“Trabectedin, as you know, is approved in many countries, most countries for soft tissue sarcoma after failing ifosfamide and doxorubicin, and then for ovarian cancer in some countries. In ovarian cancer, it’s all about sequencing so patients get lots of lines of therapy, and I think it’s appropriate to integrate this agent, which is active and tolerable into the treatment paradigm, perhaps not for every patient but for many patients, and particularly those within the 6 to 12 month platinum-free interval,” says Dr. Monk, putting the results of the new regimen into context.